Near-infrared lasers for non-invasive monitoring of glucose, ketones, HBA1C, and other blood constituents

ABSTRACT

Non-invasive monitoring of blood constituents such as glucose, ketones, or hemoglobin A1c may be accomplished using near-infrared or short-wave infrared (SWIR) light sources through absorbance, diffuse reflection, or transmission spectroscopy. As an example, hydro-carbon related substances such as glucose or ketones have distinct spectral features in the SWIR between approximately 1500 and 2500 nm. An SWIR super-continuum laser based on laser diodes and fiber optics may be used as the light source for the non-invasive monitoring. Light may be transmitted or reflected through a tooth, since an intact tooth and its enamel and dentine may be nearly transparent in the SWIR. Blood constituents or analytes within the capillaries in the dental pulp may be detected. The non-invasive monitoring device may communicate with a device such as a smart phone or tablet, which may transmit a signal related to the measurement to the cloud with cloud-based value-added services.

CROSS-REFERENCE TO RELATED APPLICATIONS

This application is the U.S. national phase of PCT Application No.PCT/US2013/075700 filed Dec. 17, 2013, which claims the benefit of U.S.provisional application Ser. No. 61/747,472 filed Dec. 31, 2012, thedisclosure of which is hereby incorporated by reference in its entirety.

This application is related to U.S. provisional application Serial Nos.61/747,477 filed Dec. 31, 2012; Ser. No. 61/747,481 filed Dec. 31, 2012;Ser. No. 61/747,485 filed Dec. 31, 2012; Ser. No. 61/747,487 filed Dec.31, 2012; Ser. No. 61/747,492 filed Dec. 31, 2012; Ser. No. 61/747,553filed Dec. 31, 2012; and Ser. No. 61/754,698 filed Jan. 21, 2013, thedisclosures of which are hereby incorporated in their entirety byreference herein.

This application has a common priority date with commonly owned U.S.application Ser. No. 14/651,367 filed Jun. 11, 2015, which is the U.S.national phase of International Application PCT/2013/075736 entitledShort-Wave Infrared Super-Continuum Lasers For Early Detection Of DentalCaries; U.S. application Ser. No. 14/108,995 filed Dec. 17, 2013entitled Focused Near-Infrared Lasers For Non-Invasive Vasectomy AndOther Thermal Coagulation Or Occlusion Procedures; U.S. application Ser.No. 14/650,981 filed Jun. 10, 2015, which is the U.S. national phase ofInternational Application PCT/2013/075767 entitled Short-Wave InfraredSuper-Continuum Lasers For Natural Gas Leak Detection, Exploration, AndOther Active Remote Sensing Applications; U.S. application Ser. No.14/108,986 filed Dec. 17, 2013 entitled Short-Wave InfraredSuper-Continuum Lasers For Detecting Counterfeit Or Illicit Drugs AndPharmaceutical Process Control; U.S. application Ser. No. 14/108,974filed Dec. 17, 2013 entitled Non-Invasive Treatment Of Varicose Veins;and U.S. application Ser. No. 14/109,007 filed Dec. 17, 2013 entitledNear-Infrared Super-Continuum Lasers For Early Detection Of Breast AndOther Cancers, the disclosures of which are hereby incorporated in theirentirety by reference herein.

TECHNICAL FIELD

This disclosure relates in general to lasers and light sources forhealthcare, medical, or bio-technology applications including systemsand methods for using near-infrared light sources for non-invasivemonitoring of different blood constituents or blood analytes, such asglucose, ketones, and hemoglobin A1C (HbA1C).

BACKGROUND AND SUMMARY

With the growing obesity epidemic, the number of individuals withdiabetes is also increasing dramatically. For example, there are over200 million people who have diabetes. Diabetes control requiresmonitoring of the glucose level, and most glucose measuring systemsavailable commercially require drawing of blood. Depending on theseverity of the diabetes, a patient may have to draw blood and measureglucose four to six times a day. This may be extremely painful andinconvenient for many people. In addition, for some groups, such assoldiers in the battlefield, it may be dangerous to have to measureperiodically their glucose level with finger pricks.

Thus, there is an unmet need for non-invasive glucose monitoring (e.g.,monitoring glucose without drawing blood). The challenge has been that anon-invasive system requires adequate sensitivity and selectivity, alongwith repeatability of the results. Yet, this is a very large market,with an estimated annual market of over $10B in 2011 for self-monitoringof glucose levels.

One approach to non-invasive monitoring of blood constituents or bloodanalytes is to use near-infrared spectroscopy, such as absorptionspectroscopy or near-infrared diffuse reflection or transmissionspectroscopy. Some attempts have been made to use broadband lightsources, such as tungsten lamps, to perform the spectroscopy. However,several challenges have arisen in these efforts. First, many otherconstituents in the blood also have signatures in the near-infrared, sospectroscopy and pattern matching, often called spectral fingerprinting,is required to distinguish the glucose with sufficient confidence.Second, the non-invasive procedures have often transmitted or reflectedlight through the skin, but skin has many spectral artifacts in thenear-infrared that may mask the glucose signatures. Moreover, the skinmay have significant water and blood content. These difficulties becomeparticularly complicated when a weak light source is used, such as alamp. More light intensity can help to increase the signal levels, and,hence, the signal-to-noise ratio.

As described in this disclosure, by using brighter light sources, suchas fiber-based supercontinuum lasers, super-luminescent laser diodes,light-emitting diodes or a number of laser diodes, the near-infraredsignal level from blood constituents may be increased. By shining lightthrough the teeth, which have fewer spectral artifacts than skin in thenear-infrared, the blood constituents may be measured with lessinterfering artifacts. Also, by using pattern matching in spectralfingerprinting and various software techniques, the signatures fromdifferent constituents in the blood may be identified. Moreover,value-add services may be provided by wirelessly communicating themonitored data to a handheld device such as a smart phone, and thenwirelessly communicating the processed data to the cloud for storing,processing, and transmitting to several locations.

SUMMARY OF EXAMPLE EMBODIMENTS

In one embodiment, a measurement system includes a light sourcegenerating an output optical beam comprising a plurality ofsemiconductor sources generating an input optical beam, a multiplexerconfigured to receive at least a portion of the input optical beam andto form an intermediate optical beam, one or more fibers configured toreceive at least a portion of the intermediate optical beam and to formthe output optical beam, wherein the output optical beam comprises oneor more optical wavelengths. An interface device is configured toreceive at least a portion of the output optical beam and to deliver theportion of the output optical beam to a sample comprising at least inpart enamel, dentine and pulp, wherein the portion of the output opticalbeam is configured to generate a spectroscopy output beam from thesample. A receiver is configured to receive at least a portion of thespectroscopy output beam and to process the portion of the spectroscopyoutput beam to generate an output signal representing at least in part aproperty of blood contained within the pulp.

In another embodiment a diagnostic system includes a light sourcegenerating an output optical beam comprising a plurality ofsemiconductor sources generating an input optical beam, a multiplexerconfigured to receive at least a portion of the input optical beam andto form an intermediate optical beam, and one or more fibers configuredto receive at least a portion of the intermediate optical beam and toform the output optical beam, wherein the output optical beam comprisesone or more optical wavelengths, wherein at least a portion of the oneor more optical wavelengths comprises a short-wave infrared wavelengthbetween approximately 1400 nanometers and approximately 2500 nanometers,and wherein at least a portion of the one of more fibers is a fusedsilica fiber with a core diameter less than approximately 400 microns.An interface device is configured to receive at least a portion of theoutput optical beam and to deliver the portion of the output opticalbeam to a sample, wherein the portion of the output optical beam isconfigured to generate a spectroscopy output beam from the sample. Areceiver is configured to receive at least a portion of the spectroscopyoutput beam having a bandwidth of at least 20 nanometers and to processthe portion of the spectroscopy output beam to generate an output signalrepresenting at least in part a property of hydro-carbon bonds.

In yet another embodiment, a method of measuring includes generating anoutput optical beam comprising generating an input optical beam from aplurality of semiconductor sources, multiplexing at least a portion ofthe input optical beam and forming an intermediate optical beam, guidingat least a portion of the intermediate optical beam and forming theoutput optical beam, wherein the output optical beam comprises one ormore optical wavelengths. The method also may include receiving at leasta portion of the output optical beam and delivering the portion of theoutput optical beam to a sample, wherein the sample comprises at leastin part enamel, dentine and pulp. The method also includes generating aspectroscopy output beam from the sample, receiving at least a portionof the spectroscopy output beam, and processing the portion of thespectroscopy output beam and generating an output signal representing atleast in part a property of blood contained within the pulp.

In one embodiment, a diagnostic system includes a light sourceconfigured to generate an output optical beam comprising one or moresemiconductor sources configured to generate an input beam, one or moreoptical amplifiers configured to receive at least a portion of the inputbeam and to deliver an intermediate beam to an output end of the one ormore optical amplifiers, and one or more optical fibers configured toreceive at least a portion of the intermediate beam and to deliver atleast the portion of the intermediate beam to a distal end of the one ormore optical fibers to form a first optical beam. A nonlinear element isconfigured to receive at least a portion of the first optical beam andto broaden a spectrum associated with the at least a portion of thefirst optical beam to at least 10 nanometers through a nonlinear effectin the nonlinear element to form the output optical beam with an outputbeam broadened spectrum, wherein at least a portion of the output beambroadened spectrum comprises a short-wave infrared wavelength betweenapproximately 1400 nanometers and approximately 2500 nanometers, andwherein at least a portion of the one of more fibers is a fused silicafiber with a core diameter less than approximately 400 microns. Aninterface device is configured to receive a received portion of theoutput optical beam and to deliver a delivered portion of the outputoptical beam to a sample, wherein the delivered portion of the outputoptical beam is configured to generate a spectroscopy output beam fromthe sample. A receiver is configured to receive at least a portion ofthe spectroscopy output beam having a bandwidth of at least 10nanometers and to process the portion of the spectroscopy output beam togenerate an output signal representing at least in part a property ofhydro-carbon bonds.

In another embodiment, a measurement system includes a light sourcegenerating an output optical beam comprising a plurality ofsemiconductor sources generating an input optical beam, a multiplexerconfigured to receive at least a portion of the input optical beam andto form an intermediate optical beam, and one or more fibers configuredto receive at least a portion of the intermediate optical beam and toform the output optical beam, wherein the output optical beam comprisesone or more optical wavelengths. An interface device is configured toreceive a received portion of the output optical beam and to deliver adelivered portion of the output optical beam to a sample comprising atleast in part enamel, dentine and pulp, wherein the delivered portion ofthe output optical beam is configured to generate a spectroscopy outputbeam from the sample. A receiver is configured to receive at least aportion of the spectroscopy output beam and to process the portion ofthe spectroscopy output beam to generate an output signal representingat least in part a property of blood contained within the pulp.

In yet another embodiment, a method of measuring includes generating anoutput optical beam comprising generating an input optical beam from aplurality of semiconductor sources, multiplexing at least a portion ofthe input optical beam and forming an intermediate optical beam, andguiding at least a portion of the intermediate optical beam and formingthe output optical beam, wherein the output optical beam comprises oneor more optical wavelengths. The method may also include receiving areceived portion of the output optical beam and delivering a deliveredportion of the output optical beam to a sample, wherein the samplecomprises at least in part enamel, dentine and pulp. The method furthermay include generating a spectroscopy output beam from the sample,receiving at least a portion of the spectroscopy output beam, andprocessing the portion of the spectroscopy output beam and generating anoutput signal representing at least in part a property of bloodcontained within the pulp.

BRIEF DESCRIPTION OF THE DRAWINGS

For a more complete understanding of the present disclosure, and forfurther features and advantages thereof, reference is now made to thefollowing description taken in conjunction with the accompanyingdrawings, in which:

FIG. 1 plots the transmittance versus wavenumber for glucose in themid-wave and long-wave infrared wavelengths between approximately 2.7 to12 microns.

FIG. 2 illustrates measurements of the absorbance of different bloodconstituents, such as glucose, hemoglobin, and hemoglobin A1c. Themeasurements are done using an FTIR spectrometer in samples with a 1 mmpath length.

FIG. 3A shows the normalized absorbance of water and glucose (not drawnto scale). Water shows transmission windows between about 1500-1850 nmand 2050-2500 nm.

FIG. 3B illustrates the absorbance of hemoglobin and oxygenatedhemoglobin overlapped with water.

FIG. 4A shows measured absorbance in different concentrations of glucosesolution over the wavelength range of about 2000 to 2400 nm. This datais collected using a SWIR super-continuum laser with the sample pathlength of about 1.1 mm.

FIG. 4B illustrates measured absorbance in different concentrations ofglucose solution over the wavelength range of about 1550 to 1800 nm. Thedata is collected using a SWIR super-continuum laser with a sample pathlength of about 10 mm.

FIG. 5 illustrates the spectrum for different blood constituents in thewavelength range of about 2 to 2.45 microns (2000 to 2450 nm).

FIG. 6 shows the transmittance versus wavelength in microns for theketone 3-hydroxybutyrate. The wavelength range is approximately 2 to 16microns.

FIG. 7 illustrates the optical absorbance for ketones as well as someother blood constituents in the wavelength range of about 2100 to 2400nm.

FIG. 8A shows the first derivative spectra of ketone and protein atconcentrations of 10 g/L (left). In addition, the first derivativespectra of urea, creatinine, and glucose are shown on the right atconcentrations of 10 g/L.

FIG. 8B illustrates the near infrared absorbance for triglyceride.

FIG. 8C shows the near-infrared reflectance spectrum for cholesterol.

FIG. 8D illustrates the near-infrared reflectance versus wavelength forvarious blood constituents, including cholesterol, glucose, albumin,uric acid, and urea.

FIG. 9 shows a schematic of the human skin. In particular, the dermismay comprise significant amounts of collagen, elastin, lipids, andwater.

FIG. 10 illustrates the absorption coefficients for water (includingscattering), adipose, collagen, and elastin.

FIG. 11 shows the dorsal of the hand, where a differential measurementmay be made to at least partially compensate for or subtract out theskin interference.

FIG. 12 shows the dorsal of the foot, where a differential measurementmay be made to at least partially compensate for or subtract out theskin interference.

FIG. 13 illustrates a typical human nail tissue structure and thecapillary vessels below it.

FIG. 14 shows the attenuation coefficient for seven nail samples thatare allowed to stand in an environment with a humidity level of 14%.These coefficients are measured using an FTIR spectrometer over thenear-infrared wavelength range of approximately 1 to 2.5 microns. Belowis also included the spectrum of glucose.

FIG. 15 illustrates the structure of a tooth.

FIG. 16A shows the attenuation coefficient for dental enamel and waterversus wavelength from approximately 600 nm to 2600 nm.

FIG. 16B illustrates the absorption spectrum of intact enamel anddentine in the wavelength range of approximately 1.2 to 2.4 microns.

FIG. 17 shows the near infrared spectral reflectance over the wavelengthrange of approximately 800 nm to 2500 nm from an occlusal tooth surface.The black diamonds correspond to the reflectance from a sound, intacttooth section. The asterisks correspond to a tooth section with anenamel lesion. The circles correspond to a tooth section with a dentinelesion.

FIG. 18A illustrates a clamp design of a human interface to cap over oneor more teeth and perform a non-invasive measurement of bloodconstituents.

FIG. 18B shows a mouth guard design of a human interface to perform anon-invasive measurement of blood constituents.

FIG. 19 illustrates a block diagram or building blocks for constructinghigh power laser diode assemblies.

FIG. 20 shows a platform architecture for different wavelength rangesfor an all-fiber-integrated, high powered, super-continuum light source.

FIG. 21 illustrates one embodiment of a short-wave infrared (SWIR)super-continuum (SC) light source.

FIG. 22 shows the output spectrum from the SWIR SC laser of FIG. 21 when˜10 m length of fiber for SC generation is used. This fiber is asingle-mode, non-dispersion shifted fiber that is optimized foroperation near 1550 nm.

FIG. 23 illustrates high power SWIR-SC lasers that may generate lightbetween approximately 1.4-1.8 microns (top) or approximately 2-2.5microns (bottom).

FIG. 24 schematically shows that the medical measurement device can bepart of a personal or body area network that communicates with anotherdevice (e.g., smart phone or tablet) that communicates with the cloud.The cloud may in turn communicate information with the user, healthcareproviders, or other designated recipients.

DETAILED DESCRIPTION

As required, detailed embodiments of the present disclosure aredisclosed herein; however, it is to be understood that the disclosedembodiments are merely exemplary of the disclosure that may be embodiedin various and alternative forms. The figures are not necessarily toscale; some features may be exaggerated or minimized to show details ofparticular components. Therefore, specific structural and functionaldetails disclosed herein are not to be interpreted as limiting, butmerely as a representative basis for teaching one skilled in the art tovariously employ the present disclosure.

Various ailments or diseases may require measurement of theconcentration of one or more blood constituents. For example, diabetesmay require measurement of the blood glucose and HbA1c levels. On theother hand, diseases or disorders characterized by impaired glucosemetabolism may require the measurement of ketone bodies in the blood.Examples of impaired glucose metabolism diseases include Alzheimer's,Parkinson's, Huntington's, and Lou Gehrig's or amyotrophic lateralsclerosis (ALS). Techniques related to near-infrared spectroscopy orhyper-spectral imaging may be particularly advantageous for non-invasivemonitoring of some of these blood constituents.

As used throughout this document, the term “couple” and or “coupled”refers to any direct or indirect communication between two or moreelements, whether or not those elements are physically connected to oneanother. As used throughout this disclosure, the term “spectroscopy”means that a tissue or sample is inspected by comparing differentfeatures, such as wavelength (or frequency), spatial location,transmission, absorption, reflectivity, scattering, refractive index, oropacity. In one embodiment, “spectroscopy” may mean that the wavelengthof the light source is varied, and the transmission, absorption orreflectivity of the tissue or sample is measured as a function ofwavelength. In another embodiment, “spectroscopy” may mean that thewavelength dependence of the transmission, absorption or reflectivity iscompared between different spatial locations on a tissue or sample. Asan illustration, the “spectroscopy” may be performed by varying thewavelength of the light source, or by using a broadband light source andanalyzing the signal using a spectrometer, wavemeter, or opticalspectrum analyzer.

As used throughout this document, the term “fiber laser” refers to alaser or oscillator that has as an output light or an optical beam,wherein at least a part of the laser comprises an optical fiber. Forinstance, the fiber in the “fiber laser” may comprise one of or acombination of a single mode fiber, a multi-mode fiber, a mid-infraredfiber, a photonic crystal fiber, a doped fiber, a gain fiber, or, moregenerally, an approximately cylindrically shaped waveguide orlight-pipe. In one embodiment, the gain fiber may be doped with rareearth material, such as ytterbium, erbium, and/or thulium. In anotherembodiment, the mid-infrared fiber may comprise one or a combination offluoride fiber, ZBLAN fiber, chalcogenide fiber, tellurite fiber, orgermanium doped fiber. In yet another embodiment, the single mode fibermay include standard single-mode fiber, dispersion shifted fiber,non-zero dispersion shifted fiber, high-nonlinearity fiber, and smallcore size fibers.

As used throughout this disclosure, the term “pump laser” refers to alaser or oscillator that has as an output light or an optical beam,wherein the output light or optical beam is coupled to a gain medium toexcite the gain medium, which in turn may amplify another input opticalsignal or beam. In one particular example, the gain medium may be adoped fiber, such as a fiber doped with ytterbium, erbium or thulium. Inone embodiment, the “pump laser” may be a fiber laser, a solid statelaser, a laser involving a nonlinear crystal, an optical parametricoscillator, a semiconductor laser, or a plurality of semiconductorlasers that may be multiplexed together. In another embodiment, the“pump laser” may be coupled to the gain medium by using a fiber coupler,a dichroic mirror, a multiplexer, a wavelength division multiplexer, agrating, or a fused fiber coupler.

As used throughout this document, the term “super-continuum” and or“supercontinuum” and or “SC” refers to a broadband light beam or outputthat comprises a plurality of wavelengths. In a particular example, theplurality of wavelengths may be adjacent to one-another, so that thespectrum of the light beam or output appears as a continuous band whenmeasured with a spectrometer. In one embodiment, the broadband lightbeam may have a bandwidth of at least 10 nm. In another embodiment, the“super-continuum” may be generated through nonlinear opticalinteractions in a medium, such as an optical fiber or nonlinear crystal.For example, the “super-continuum” may be generated through one or acombination of nonlinear activities such as four-wave mixing, the Ramaneffect, modulational instability, and self-phase modulation.

As used throughout this disclosure, the terms “optical light” and or“optical beam” and or “light beam” refer to photons or light transmittedto a particular location in space. The “optical light” and or “opticalbeam” and or “light beam” may be modulated or unmodulated, which alsomeans that they may or may not contain information. In one embodiment,the “optical light” and or “optical beam” and or “light beam” mayoriginate from a fiber, a fiber laser, a laser, a light emitting diode,a lamp, a pump laser, or a light source.

Spectrum for Glucose

One molecule of interest is glucose. The glucose molecule has thechemical formula C₆H₁₂O₆, so it has a number of hydro-carbon bonds. Anexample of the infrared transmittance of glucose 100 is illustrated inFIG. 1. The vibrational spectroscopy shows that the strongest lines forbending and stretching modes of C—H and O—H bonds lie in the wavelengthrange of approximately 6-12 microns. However, light sources anddetectors are more difficult in the mid-wave infrared and long-waveinfrared, and there is also strongly increasing water absorption in thehuman body beyond about 2.5 microns. Although weaker, there are alsonon-linear combinations of stretching and bending modes between about 2to 2.5 microns, and first overtone of C—H stretching modes betweenapproximately 1.5-1.8 microns. These signatures may fall in valleys ofwater absorption, permitting non-invasive detection through the body. Inaddition, there are yet weaker features from the second overtones andhigher-order combinations between about 0.8-1.2 microns; in addition tobeing weaker, these features may also be masked by absorption in thehemoglobin. Hence, the short-wave infrared (SWIR) wavelength range ofapproximately 1.4 to 2.5 microns may be an attractive window fornear-infrared spectroscopy of blood constituents.

As an example, measurements of the optical absorbance 200 of hemoglobin,glucose and HbA1c have been performed using a Fourier-Transform InfraredSpectrometer—FTIR. As FIG. 2 shows, in the SWIR wavelength rangehemoglobin is nearly flat in spectrum 201 (the noise at the edges is dueto the weaker light signal in the measurements). On the other hand, theglucose absorbance 202 has at least five distinct peaks near 1587 nm,1750 nm, 2120 nm, 2270 nm and 2320 nm.

FIG. 3A overlaps 300 the normalized absorbance of glucose 301 with theabsorbance of water 302 (not drawn to scale). It may be seen that waterhas an absorbance feature between approximately 1850 nm and 2050 nm, butwater 302 also has a nice transmission window between approximately1500-1850 nm and 2050 to 2500 nm. For wavelengths less than about 1100nm, the absorption of hemoglobin 351 and oxygenated hemoglobin 352 inFIG. 3B has a number of features 350, which may make it more difficultto measure blood constituents. Also, beyond 2500 nm the water absorptionbecomes considerably stronger over a wide wavelength range. Therefore,an advantageous window for measuring glucose and other bloodconstituents may be in the SWIR between 1500 and 1850 nm and 2050 to2500 nm. These are exemplary wavelength ranges, and other ranges can beused that would still fall within the scope of this disclosure.

One further consideration in choosing the laser wavelength is known asthe “eye safe” window for wavelengths longer than about 1400 nm. Inparticular, wavelengths in the eye safe window may not transmit down tothe retina of the eye, and therefore, these wavelengths may be lesslikely to create permanent eye damage. The near-infrared wavelengthshave the potential to be dangerous, because the eye cannot see thewavelengths (as it can in the visible), yet they can penetrate and causedamage to the eye. Even if a practitioner is not looking directly at thelaser beam, the practitioner's eyes may receive stray light from areflection or scattering from some surface. Hence, it can always be agood practice to use eye protection when working around lasers. Sincewavelengths longer than about 1400 nm are substantially not transmittedto the retina or substantially absorbed in the retina, this wavelengthrange is known as the eye safe window. For wavelengths longer than 1400nm, in general only the cornea of the eye may receive or absorb thelight radiation.

Beyond measuring blood constituents such as glucose using FTIRspectrometers, measurements have also been conducted in anotherembodiment using super-continuum lasers, which will be described laterin this disclosure. In this particular embodiment, some of the exemplarypreliminary data for glucose absorbance are illustrated in FIGS. 4A and4B. The optical spectra 401 in FIG. 4A for different levels of glucoseconcentration in the wavelength range between 2000 and 2400 nm show thethree absorption peaks near 2120 nm (2.12 μm), 2270 nm (2.27 μm) and2320 nm (2.32 μm). Moreover, the optical spectra 402 in FIG. 4B fordifferent levels of glucose concentration in the wavelength rangebetween 1500 and 1800 nm show the two broader absorption peaks near 1587nm and 1750 nm. It should be appreciated that although data measuredwith FTIR spectrometers or super-continuum lasers have been illustrated,other light sources can also be used to obtain the data, such assuper-luminescent laser diodes, light emitting diodes, a plurality oflaser diodes, or even bright lamp sources that generate adequate lightin the SWIR.

Although glucose has a distinctive signature in the SWIR wavelengthrange, one problem of non-invasive glucose monitoring is that many otherblood constituents also have hydro-carbon bonds. Consequently, there canbe interfering signals from other constituents in the blood. As anexample, FIG. 5 illustrates the spectrum 500 for different bloodconstituents in the wavelength range of 2 to 2.45 microns. The glucoseabsorption spectrum 501 can be unique with its three peaks in thiswavelength range. However, other blood constituents such as triacetin502, ascorbate 503, lactate 504, alanine 505, urea 506, and BSA 507 alsohave spectral features in this wavelength range. To distinguish theglucose 501 from these overlapping spectra, it may be advantageous tohave information at multiple wavelengths. In addition, it may beadvantageous to use pattern matching algorithms and other software andmathematical methods to identify the blood constituents of interest. Inone embodiment, the spectrum may be correlated with a library of knownspectra to determine the overlap integrals, and a threshold function maybe used to quantify the concentration of different constituents. This isjust one way to perform the signal processing, and many othertechniques, algorithms, and software may be used and would fall withinthe scope of this disclosure.

Ketone Bodies Monitoring

Beyond glucose, there are many other blood constituents that may also beof interest for health or disease monitoring. In another embodiment, itmay be desirous to monitor the level of ketone bodies in the bloodstream. Ketone bodies are three water-soluble compounds that areproduced as by-products when fatty acids are broken down for energy inthe liver. Two of the three are used as a source of energy in the heartand brain, while the third is a waste product excreted from the body. Inparticular, the three endogenous ketone bodies are acetone, acetoaceticacid, and beta-hydroxybutyrate or 3-hydroxybutyrate, and the wasteproduct ketone body is acetone.

Ketone bodies may be used for energy, where they are transported fromthe liver to other tissues. The brain may utilize ketone bodies whensufficient glucose is not available for energy. For instance, this mayoccur during fasting, strenuous exercise, low carbohydrate, ketogenicdiet and in neonates. Unlike most other tissues that have additionalenergy sources such as fatty acids during periods of low blood glucose,the brain cannot break down fatty acids and relies instead on ketones.In one embodiment, these ketone bodies are detected.

Ketone bodies may also be used for reducing or eliminating symptoms ofdiseases or disorders characterized by impaired glucose metabolism. Forexample, diseases associated with reduced neuronal metabolism of glucoseinclude Parkinson's disease, Alzheimer's disease, amyotrophic lateralsclerosis (ALS, also called Lou Gehrig's disease), Huntington's diseaseand epilepsy. In one embodiment, monitoring of alternate sources ofketone bodies that may be administered orally as a dietary supplement orin a nutritional composition to counteract some of the glucosemetabolism impairments is performed. However, if ketone bodiessupplements are provided, there is also a need to monitor the ketonelevel in the blood stream. For instance, if elevated levels of ketonebodies are present in the body, this may lead to ketosis; hyperketonemiais also an elevated level of ketone bodies in the blood. In addition,both acetoacetic acid and beta-hydroxybutyric acid are acidic, and, iflevels of these ketone bodies are too high, the pH of the blood maydrop, resulting in ketoacidosis.

The general formula for ketones is C_(n)H_(2n)0. In organic chemistry, aketone is an organic compound with the structure RC(═O)R′, where R andR′ can be a variety of carbon-containing substituents. It features acarbonyl group (C═O) bonded to two other carbon atoms. Because theketones contain the hydrocarbon bonds, there might be expected to befeatures in the SWIR, similar in structure to those found for glucose.

The infrared spectrum 600 for the ketone 3-hydroxybutyrate isillustrated in FIG. 6. Just as in glucose, there are significantfeatures in the mid- and long-wave infrared between 6 to 12 microns, butthese may be difficult to observe non-invasively. On the other hand,there are some features in the SWIR that may be weaker, but they couldpotentially be observed non-invasively, perhaps through blood and water.

The optical spectra 700 for ketones as well as some other bloodconstituents are exemplified in FIG. 7 in the wavelength range of 2100nm to 2400 nm. In this embodiment, the absorbance for ketones is 701,while the absorbance for glucose is 702. However, there are alsofeatures in this wavelength range for other blood constituents, such asurea 703, albumin or blood protein 704, creatinine 705, and nitrite 706.In this wavelength range of 2100 to 2400 nm, the features for ketone 701seem more spectrally pronounced than even glucose.

Different signal processing techniques can be used to enhance thespectral differences between different constituents. In one embodiment,the first or second derivatives of the spectra may enable betterdiscrimination between substances. The first derivative may help removeany flat offset or background, while the second derivative may help toremove any sloped offset or background. In some instances, the first orsecond derivative may be applied after curve fitting or smoothing thereflectance, transmittance, or absorbance. For example, FIG. 8Aillustrates the derivative spectra for ketone 801 and glucose 802, whichcan be distinguished from the derivative spectra for protein 803, urea804 and creatinine 805. Based on FIG. 8A, it appears that ketones 801may have a more pronounced difference than even glucose 802 in thewavelength range between 2100 and 2400 nm. Therefore, ketone bodiesshould also be capable of being monitored using a non-invasive opticaltechnique in the SWIR, and a different pattern matching library could beused for glucose and ketones.

Hemoglobin A1c Monitoring

Another blood constituent that may be of interest for monitoring ofhealth or diseases is hemoglobin A1c, also known as HbA1c or glycatedhemoglobin (glycol-hemoglobin or glycosylated hemoglobin). HbA1c is aform of hemoglobin that is measured primarily to identify the averageplasma glucose concentration over prolonged periods of time. Thus, HbA1cmay serve as a marker for average blood glucose levels over the previousmonths prior to the measurements.

In one embodiment, when a physician suspects that a patient may bediabetic, the measurement of HbA1c may be one of the first tests thatare conducted. An HbA1c level less than approximately 6% may beconsidered normal. On the other hand, an HbA1c level greater thanapproximately 6.5% may be considered to be diabetic. In diabetesmellitus, higher amounts of HbA1c indicate poorer control of bloodglucose levels. Thus, monitoring the HbA1c in diabetic patients mayimprove treatment. Current techniques for measuring HbA1c requiredrawing blood, which may be inconvenient and painful. The point-of-caredevices use immunoassay or boronate affinity chromatography, as anexample. Thus, there is also an unmet need for non-invasive monitoringof HbA1c.

FIG. 2 illustrates the FTIR measurements of HbA1c absorbance 203 overthe wavelength range between 1500 and 2400 nm for a concentration ofapproximately 1 mg/ml. Whereas the absorbance of hemoglobin 201 overthis wavelength range is approximately flat, the HbA1c absorbance 203shows broad features and distinct curvature. Although the HbA1cabsorbance 203 does not appear to exhibit as pronounced features asglucose 202, the non-invasive SWIR measurement should be able to detectHbA1c with appropriate pattern matching algorithms. Moreover, thespectrum for HbA1c may be further enhanced by using first or secondderivative data, as seen for ketones in FIG. 8A. Beyond absorption,reflectance, or transmission spectroscopy, it may also be possible todetect blood constituents such as HbA1c using Raman spectroscopy orsurface-enhanced Raman spectroscopy. In general, Raman spectroscopy mayrequire higher optical power levels.

As an illustration, non-invasive measurement of blood constituents suchas glucose, ketone bodies, and HbA1c has been discussed thus far.However, other blood constituents can also be measured using similartechniques, and these are also intended to be covered by thisdisclosure. In other embodiments, blood constituents such as proteins,albumin, urea, creatinine or nitrites could also be measured. Forinstance, the same type of SWIR optical techniques might be used, butthe pattern matching algorithms and software could use different libraryfeatures or functions for the different constituents.

In yet another embodiment, the optical techniques described in thisdisclosure could also be used to measure levels of triglycerides.Triglycerides are bundles of fats that may be found in the blood stream,particularly after ingesting meals. The body manufactures triglyceridesfrom carbohydrates and fatty foods that are eaten. In other words,triglycerides are the body's storage form of fat. Triglycerides arecomprised of three fatty acids attached to a glycerol molecule, andmeasuring the level of triglycerides may be important for diabetics. Thetriglyceride levels or concentrations in blood may be rated as follows:desirable or normal may be less than 150 mg/dl; borderline high may be150-199 mg/dl; high may be 200-499 mg/dl; and very high may be 500 mg/dlor greater. FIG. 8B illustrates one example of the near-infraredabsorbance 825 for triglycerides. There are distinct absorbance peaks inthe spectrum that should be measurable. The characteristic absorptionbands may be assigned as follows: (a) the first overtones of C—Hstretching vibrations (1600-1900 nm); (b) the region of second overtonesof C—H stretching vibrations (1100-1250 nm); and, (c) two regions(2000-2200 nm and 1350-1500 nm) that comprise bands due to combinationsof C—H stretching vibrations and other vibrational modes.

A further example of blood compositions that can be detected or measuredusing near-infrared light includes cholesterol monitoring. For example,FIG. 8C shows the near-infrared reflectance spectrum for cholesterol 850with wavelength in microns (μm). Distinct absorption peaks areobservable near 1210 nm (1.21 μm), 1720 nm (1.72 μm), and between2300-2500 nm (2.3-2.5 μm). Also, there are other features near 1450 nm(1.45 μm) and 2050 nm (2.05 μm). In FIG. 8D the near-infraredreflectances 875 are displayed versus wavelength (nm) for various bloodconstituents. The spectrum for cholesterol 876 is overlaid with glucose877, albumin 878, uric acid 879, and urea 880. As may be noted from FIG.8D, at about 1720 nm and 2300 nm, cholesterol 876 reaches approximatereflectance peaks, while some of the other analytes are in a moregradual mode. Various signal processing methods may be used to identifyand quantify the concentration of cholesterol 876 and/or glucose 877, orsome of the other blood constituents.

As illustrated by FIGS. 5 and 7, one of the issues in measuring aparticular blood constituent is the interfering and overlapping signalfrom other blood constituents. The selection of the constituent ofinterest may be improved using a number of techniques. For example, ahigher light level or intensity may improve the signal-to-noise ratiofor the measurement. Second, mathematical modeling and signal processingmethodologies may help to reduce the interference, such as multivariatetechniques, multiple linear regression, and factor-based algorithms, forexample. For instance, a number of mathematical approaches includemultiple linear regression, partial least squares, and principalcomponent regression (PCR). Also, as illustrated in FIG. 8A, variousmathematical derivatives, including the first and second derivatives,may help to accentuate differences between spectra. In addition, byusing a wider wavelength range and using more sampling wavelengths mayimprove the ability to discriminate one signal from another. These arejust examples of some of the methods of improving the ability todiscriminate between different constituents, but other techniques mayalso be used and are intended to be covered by this disclosure.

Interference from Skin

Several proposed non-invasive glucose monitoring techniques rely ontransmission, absorption, and/or diffuse reflection through the skin tomeasure blood constituents or blood analytes in veins, arteries,capillaries or in the tissue itself. However, on top of the interferencefrom other blood constituents or analytes, the skin also introducessignificant interference. For example, chemical, structural, andphysiological variations occur that may produce relatively large andnonlinear changes in the optical properties of the tissue sample. In oneembodiment, the near-infrared reflectance or absorbance spectrum may bea complex combination of the tissue scattering properties that resultfrom the concentration and characteristics of a multiplicity of tissuecomponents including water, fat, protein, collagen, elastin, and/orglucose. Moreover, the optical properties of the skin may also changewith environmental factors such as humidity, temperature and pressure.Physiological variation may also cause changes in the tissue measurementover time and may vary based on lifestyle, health, aging, etc. Thestructure and composition of skin may also vary widely amongindividuals, between different sites within an individual, and over timeon the same individual. Thus, the skin introduces a dynamic interferencesignal that may have a wide variation due to a number of parameters.

FIG. 9 shows a schematic cross-section of human skin 900, 901. The toplayer of the skin is epidermis 902, followed by a layer of dermis 903and then subcutaneous fat 904 below the dermis. The epidermis 902, witha thickness of approximately 10-150 microns, may provide a barrier toinfection and loss of moisture and other body constituents. The dermis903 ranges in thickness from approximately 0.5 mm to 4 mm (averagesapproximately 1.2 mm over most of the body) and may provide themechanical strength and elasticity of skin.

In the dermis 903, water may account for approximately 70% of thevolume. The next most abundant constituent in the dermis 903 may becollagen 905, a fibrous protein comprising 70-75% of the dry weight ofthe dermis 903. Elastin fibers 906, also a protein, may also beplentiful in the dermis 903, although they constitute a smaller portionof the bulk. In addition, the dermis 903 may contain a variety ofstructures (e.g., sweat glands, hair follicles with adipose richsebaceous glands 907 near their roots, and blood vessels) and othercellular constituents.

Below the dermis 903 lies the subcutaneous layer 904 comprising mostlyadipose tissue. The subcutaneous layer 904 may be by volumeapproximately 10% water and may be comprised primarily of cells rich intriglycerides or fat. With this complicated structure of the skin 900,901, the concentration of glucose may vary in each layer according to avariety of factors including the water content, the relative sizes ofthe fluid compartments, the distribution of capillaries, the perfusionof blood, the glucose uptake of cells, the concentration of glucose inblood, and the driving forces (e.g., osmotic pressure) behind diffusion.

To better understand the interference that the skin introduces whenattempting to measure glucose, the absorption coefficient for thevarious skin constituents should be examined. For example, FIG. 10illustrates 1000 the absorption coefficients for water (includingscattering) 1001, adipose 1002, collagen 1003 and elastin 1004. Notethat the absorption curves for water 1001 and adipose 1002 arecalibrated, whereas the absorption curves for collagen 1003 and elastin1004 are in arbitrary units. Also shown are vertical lines demarcatingthe wavelengths near 1210 nm 1005 and 1720 nm 1006. In general, thewater absorption increases with increasing wavelength. With theincreasing absorption beyond about 2000 nm, it may be difficult toachieve deeper penetration into biological tissue in the infraredwavelengths beyond approximately 2500 nm.

Although the absorption coefficient may be useful for determining thematerial in which light of a certain infrared wavelength will beabsorbed, to determine the penetration depth of the light of a certainwavelength may also require the addition of scattering loss to thecurves. For example, the water curve 1001 includes the scattering losscurve in addition to the water absorption. In particular, the scatteringloss can be significantly higher at shorter wavelengths. In oneembodiment, near the wavelength of 1720 nm (vertical line 1006 shown inFIG. 10), the adipose absorption 1002 can still be higher than the waterplus scattering loss 1001. For tissue that contains adipose, collagenand elastin, such as the dermis of the skin, the total absorption canexceed the light energy lost to water absorption and light scattering at1720 nm. On the other hand, at 1210 nm the adipose absorption 1002 canbe considerably lower than the water plus scattering loss 1001,particularly since the scattering loss can be dominant at these shorterwavelengths.

The interference for glucose lines observed through skin may beillustrated by overlaying the glucose lines over the absorption curves1000 for the skin constituents. For example, FIG. 2 illustrated that theglucose absorption 202 included features centered around 1587 nm, 1750nm, 2120 nm, 2270 nm and 2320 nm. On FIG. 10 vertical lines have beendrawn at the glucose line wavelengths of 1587 nm 1007, 1750 nm 1008,2120 nm 1009, 2270 nm 1010 and 2320 nm 1011. In one embodiment, it maybe difficult to detect the glucose lines near 1750 nm 1008, 2270 nm 1010and 2320 nm 1011 due to significant spectral interference from otherskin constituents. On the other hand, the glucose line near 1587m 1007may be more easily detected because it peaks while most of the otherskin constituents are sloped downward toward an absorption valley.Moreover, the glucose line near 2120 nm 1009 may also be detectable forsimilar reasons, although adipose may have conflicting behavior due tolocal absorption minimum and maximum nearby in wavelength.

Thus, beyond the problem of other blood constituents or analytes havingoverlapping spectral features (e.g., FIG. 5), it may be difficult toobserve glucose spectral signatures through the skin and itsconstituents of water, adipose, collagen and elastin. One approach toovercoming this difficulty may be to try to measure the bloodconstituents in veins that are located at relatively shallow distancesbelow the skin. Veins may be more beneficial for the measurement thanarteries, since arteries tend to be located at deeper levels below theskin. Also, in one embodiment it may be advantageous to use adifferential measurement to subtract out some of the interferingabsorption lines from the skin. For example, an instrument head may bedesigned to place one probe above a region of skin over a blood vein,while a second probe may be placed at a region of the skin without anoticeable blood vein below it. Then, by differencing the signals fromthe two probes, at least part of the skin interference may be cancelledout.

Two representative embodiments for performing such a differentialmeasurement are illustrated in FIG. 11 and FIG. 12. In one embodimentshown in FIG. 11, the dorsal of the hand 1100 may be used for measuringblood constituents or analytes. The dorsal of the hand 1100 may haveregions that have distinct veins 1101 as well as regions where the veinsare not as shallow or pronounced 1102. By stretching the hand andleaning it backwards, the veins 1101 may be accentuated in some cases. Anear-infrared diffuse reflectance measurement may be performed byplacing one probe 1103 above the vein-rich region 1101. To turn thisinto a differential measurement, a second probe 1104 may be placed abovea region without distinct veins 1102. Then, the outputs from the twoprobes may be subtracted 1105 to at least partially cancel out thefeatures from the skin. The subtraction may be done preferably in theelectrical domain, although it can also be performed in the opticaldomain or digitally/mathematically using sampled data based on theelectrical and/or optical signals. Although one example of using thedorsal of the hand 1100 is shown, many other parts of the hand can beused within the scope of this disclosure. For example, alternate methodsmay use transmission through the webbing between the thumb and thefingers 1106, or transmission or diffuse reflection through the tips ofthe fingers 1107.

In another embodiment, the dorsal of the foot 1200 may be used insteadof the hand. One advantage of such a configuration may be that forself-testing by a user, the foot may be easier to position theinstrument using both hands. One probe 1203 may be placed over regionswhere there are more distinct veins 1201, and a near-infrared diffusereflectance measurement may be made. For a differential measurement, asecond probe 1204 may be placed over a region with less prominent veins1202, and then the two probe signals may be subtracted, eitherelectronically or optically, or may be digitized/sampled and processedmathematically depending on the particular application andimplementation. As with the hand, the differential measurements may beintended to compensate for or subtract out (at least in part) theinterference from the skin. Since two regions are used in closeproximity on the same body part, this may also aid in removing somevariability in the skin from environmental effects such as temperature,humidity, or pressure. In addition, it may be advantageous to firsttreat the skin before the measurement, by perhaps wiping with a cloth ortreated cotton ball, applying some sort of cream, or placing an ice cubeor chilled bag over the region of interest.

Although two embodiments have been described, many other locations onthe body may be used using a single or differential probe within thescope of this disclosure. In yet another embodiment, the wrist may beadvantageously used, particularly where a pulse rate is typicallymonitored. Since the pulse may be easily felt on the wrist, there isunderlying the region a distinct blood flow. Other embodiments may useother parts of the body, such as the ear lobes, the tongue, the innerlip, the nails, the eye, or the teeth. Some of these embodiments will befurther described below. The ear lobes or the tip of the tongue may beadvantageous because they are thinner skin regions, thus permittingtransmission rather than diffuse reflection. However, the interferencefrom the skin is still a problem in these embodiments. Other regionssuch as the inner lip or the bottom of the tongue may be contemplatedbecause distinct veins are observable, but still the interference fromthe skin may be problematic in these embodiments. The eye may seem as aviable alternative because it is more transparent than skin. However,there are still issues with scattering in the eye. For example, theanterior chamber of the eye (the space between the cornea and the iris)comprises a fluid known as aqueous humor. However, the glucose level inthe eye chamber may have a significant temporal lag on changes in theglucose level compared to the blood glucose level.

Because of the complexity of the interference from skin in non-invasiveglucose monitoring (e.g., FIG. 10), other parts of the body without skinabove blood vessels or capillaries may be alternative candidates formeasuring blood constituents. One embodiment may involve transmission orreflection through human nails. As an example, FIG. 13 illustrates atypical human nail tissue structure 1300 and the capillary vessels belowit. The fingernail 1301 is approximately 1 mm thick, and below thisresides a layer of epidermis 1302 with a thickness of approximately 1mm. The dermis 1304 is also shown, and within particularly the top about0.5 mm of dermis are a significant number of capillary vessels. Tomeasure the blood constituents, the light exposed on the top of thefingernail must penetrate about 2-2.5 mm or more, and the reflectedlight (round trip passage) should be sufficiently strong to measure. Inone embodiment, the distance required to penetrate could be reduced bydrilling a hole in the fingernail 1301.

In this alternative embodiment using the fingernail, there may still beinterference from the nail's spectral features. For example, FIG. 14illustrates the attenuation coefficient 1400 for seven nail samples thatare allowed to stand in an environment with a humidity level of 14%.These coefficients are measured using an FTIR spectrometer over thenear-infrared wavelength range of approximately 1 to 2.5 microns. Thesespectra are believed to correspond to the spectra of keratin containedin the nail plate. The base lines for the different samples are believedto differ because of the influence of scattering. Several of theabsorption peaks observed correspond to peaks of keratin absorption,while other features may appear from the underlying epidermis anddermis. It should also be noted that the attenuation coefficients 1400also vary considerably depending on humidity level or water content aswell as temperature and other environmental factors. Moreover, theattenuation coefficient may also change in the presence of nail polishof various sorts.

Similar to skin, the large variations in attenuation coefficient forfingernails also may interfere with the absorption peaks of glucose. Asan example, in FIG. 14 below the fingernail spectrum is also shown theglucose spectrum 1401 for two different glucose concentrations. Thevertical lines 1402, 1403, 1404, 1405 and 1406 are drawn to illustratethe glucose absorption peaks and where they lie on the fingernailspectra 1400. As is apparent, the nail has interfering features that maybe similar to skin, particularly since both have spectra that vary notonly in wavelength but also with environmental factors. In oneembodiment, it may be possible to see the glucose peaks 1402 and 1404through the fingernail, but it may be much more difficult to observe theglucose peaks near 1403, 1405 and 1406.

Transmission or Reflection Through Teeth

Yet another embodiment may observe the transmittance or reflectancethrough teeth to measure blood constituents or analytes. FIG. 15illustrates an exemplary structure of a tooth 1500. The tooth 1500 has atop layer called the crown 1501 and below that a root 1502 that reacheswell into the gum 1506 and bone 1508 of the mouth. The exterior of thecrown 1501 is an enamel layer 1503, and below the enamel is a layer ofdentine 1504 that sits atop a layer of cementum 1507. Below the dentine1504 is a pulp region 1505, which comprises within it blood vessels 1509and nerves 1510. If the light can penetrate the enamel 1503 and dentine1504, then the blood flow and blood constituents can be measured throughthe blood vessels in the dental pulp 1505. While it may be true that theamount of blood flow in the dental pulp 1505 may be less since itcomprises capillaries, the smaller blood flow could still beadvantageous if there is less interfering spectral features from thetooth.

The transmission, absorption and reflection from teeth has been studiedin the near infrared, and, although there are some features, the enameland dentine appear to be fairly transparent in the near infrared(particularly wavelengths between 1500 and 2500 nm). For example, theabsorption or extinction ratio for light transmission has been studied.FIG. 16A illustrates the attenuation coefficient 1600 for dental enamel1601 (filled circles) and the absorption coefficient of water 1602 (opencircles) versus wavelength. Near-infrared light may penetrate muchfurther without scattering through all the tooth enamel, due to thereduced scattering coefficient in normal enamel. Scattering in enamelmay be fairly strong in the visible, but decreases as approximately1/(wavelength)3 [i.e., inverse of the cube of the wavelength] withincreasing wavelength to a value of only 2-3 cm-1 at 1310 nm and 1550 nmin the near infrared. Therefore, enamel may be virtually transparent inthe near infrared with optical attenuation 1-2 orders of magnitude lessthan in the visible range.

As another example, FIG. 16B illustrates the absorption spectrum 1650 ofintact enamel 1651 (dashed line) and dentine 1652 (solid line) in thewavelength range of approximately 1.2 to 2.4 microns. In the nearinfrared there are two absorption bands around 1.5 and 2 microns. Theband with a peak around 1.57 microns may be attributed to the overtoneof valent vibration of water present in both enamel and dentine. In thisband, the absorption is greater for dentine than for enamel, which maybe related to the large water content in this tissue. In the region of 2microns, dentine may have two absorption bands, and enamel one. The bandwith a maximum near 2.1 microns may belong to the overtone of vibrationof PO hydroxyapatite groups, which is the main substance of both enameland dentine. Moreover, the band with a peak near 1.96 microns in dentinemay correspond to water absorption (dentine may contain substantiallyhigher water than enamel).

In addition to the absorption coefficient, the reflectance from intactteeth and teeth with dental caries (e.g., cavities) has been studied. Inone embodiment, FIG. 17 shows the near infrared spectral reflectance1700 over the wavelength range of approximately 800 nm to 2500 nm froman occlusal (e.g., top/bottom) tooth surface 1704. The curve with blackdiamonds 1701 corresponds to the reflectance from a sound, intact toothsection. The curve with asterisks * 1702 corresponds to a tooth sectionwith an enamel lesion. The curve with circles 1703 corresponds to atooth section with a dentine lesion. Thus, when there is a lesion, morescattering occurs and there may be an increase in the reflected light.

For wavelengths shorter than approximately 1400 nm, the shapes of thespectra remain similar, but the amplitude of the reflection changes withlesions. Between approximately 1400 nm and 2500 nm, an intact tooth 1701has low reflectance (e.g., high transmission), and the reflectanceappears to be more or less independent of wavelength. On the other hand,in the presence of lesions 1702 and 1703, there is increased scattering,and the scattering loss may be wavelength dependent. For example, thescattering loss may decrease as 1/(wavelength)³—so, the scattering lossdecreases with longer wavelengths. When there is a lesion in the dentine1703, more water can accumulate in the area, so there is also increasedwater absorption. For example, the dips near 1450 nm and 1900 nmcorrespond to water absorption, and the reflectance dips areparticularly pronounced in the dentine lesion 1703. One other benefit ofthe absorption, transmission or reflectance in the near infrared may bethat stains and non-calcified plaque are not visible in this wavelengthrange, enabling better discrimination of defects, cracks, anddemineralized areas.

Compared with the interference from skin 1000 in FIG. 10 or fingernails1400 in FIG. 14, the teeth appear to introduce much less interferencefor non-invasive monitoring of blood constituents. The few features inFIG. 16B or 17 may be calibrated out of the measurement. Also, using anintact tooth 1701 may further minimize any interfering signals.Furthermore, since the tooth comprises relatively hard tissue, higherpower from the light sources in the near infrared may be used withoutdamaging the tissue, such as with skin.

Human Interface for Measurement System

A number of different types of measurements may be used to sample theblood in the dental pulp. The basic feature of the measurements shouldbe that the optical properties are measured as a function of wavelengthat a plurality of wavelengths. As further described below, the lightsource may output a plurality of wavelengths, or a continuous spectrumover a range of wavelengths. In a preferred embodiment, the light sourcemay cover some or all of the wavelength range between approximately 1400nm and 2500 nm. The signal may be received at a receiver, which may alsocomprise a spectrometer or filters to discriminate between differentwavelengths. The signal may also be received at a camera, which may alsocomprise filters or a spectrometer. In an alternate embodiment, thespectral discrimination using filters or a spectrometer may be placedafter the light source rather than at the receiver. The receiver usuallycomprises one or more detectors (optical-to-electrical conversionelement) and electrical circuitry. The receiver may also be coupled toanalog to digital converters, particularly if the signal is to be fed toa digital device.

Referring to FIG. 15, one or more light sources 1511 may be used forillumination. In one embodiment, a transmission measurement may beperformed by directing the light source output 1511 to the region nearthe interface between the gum 1506 and dentine 1504. In one embodiment,the light may be directed using a light guide or a fiber optic. Thelight may then propagate through the dental pulp 1505 to the other side,where the light may be incident on one or more detectors or anotherlight guide to transport the signal to a spectrometer, receiver orcamera 1512. In another embodiment, the light source may be directed toone or more locations near the interface between the gum 1506 anddentine 1504 (in one example, could be from the two sides of the tooth).The transmitted light may then be detected in the occlusal surface abovethe tooth using a spectrometer, receiver, or camera 1512. In yet anotherembodiment, a reflectance measurement may be conducted by directing thelight source output 1511 to, for example, the occlusal surface of thetooth, and then detecting the reflectance at a spectrometer, receiver orcamera 1513. Although a few embodiments for measuring the bloodconstituents through a tooth are described, other embodiments andtechniques may also be used and are intended to be covered by thisdisclosure.

The human interface for the non-invasive measurement of bloodconstituents may be of various forms. In one embodiment, a “clamp”design 1800 may be used cap over one or more teeth, as illustrated inFIG. 18A. The clamp design may be different for different types ofteeth, or it may be flexible enough to fit over different types ofteeth. For example, different types of teeth include the molars (towardthe back of the mouth), the premolars, the canine, and the incisors(toward the front of the mouth). One embodiment of the clamp-type designis illustrated in FIG. 18A for a molar tooth 1808. The C-clamp 1801 maybe made of a plastic or rubber material, and it may comprise a lightsource input 1802 and a detector output 1803 on the front or back of thetooth.

The light source input 1802 may comprise a light source directly, or itmay have light guided to it from an external light source. Also, thelight source input 1802 may comprise a lens system to collimate or focusthe light across the tooth. The detector output 1803 may comprise adetector directly, or it may have a light guide to transport the signalto an external detector element. The light source input 1802 may becoupled electrically or optically through 1804 to a light input 1806.For example, if the light source is external in 1806, then the couplingelement 1804 may be a light guide, such as a fiber optic. Alternately,if the light source is contained in 1802, then the coupling element 1804may be electrical wires connecting to a power supply in 1806. Similarly,the detector output 1803 may be coupled to a detector output unit 1807with a coupling element 1805, which may be one or more electrical wiresor a light guide, such as a fiber optic. This is just one example of aclamp over one or more teeth, but other embodiments may also be used andare intended to be covered by this disclosure.

In yet another embodiment, one or more light source ports and sensorports may be used in a mouth-guard type design. For example, oneembodiment of a dental mouth guard 1850 is illustrated in FIG. 18B. Thestructure of the mouth guard 1851 may be similar to mouth guards used insports (e.g., when playing football or boxing) or in dental trays usedfor applying fluoride treatment, and the mouth guard may be made fromplastic or rubber materials, for example. As an example, the mouth guardmay have one or more light source input ports 1852, 1853 and one or moredetector output ports 1854, 1855. Although six input and output portsare illustrated, any number of ports may be used.

Similar to the clamp design describe above, the light source inputs1852, 1853 may comprise one or more light sources directly, or they mayhave light guided to them from an external light source. Also, the lightsource inputs 1852, 1853 may comprise lens systems to collimate or focusthe light across the teeth. The detector outputs 1854, 1855 may compriseone or more detectors directly, or they may have one or more lightguides to transport the signals to an external detector element. Thelight source inputs 1852, 1853 may be coupled electrically or opticallythrough 1856 to a light input 1857. For example, if the light source isexternal in 1857, then the one or more coupling elements 1856 may be oneor more light guides, such as a fiber optic. Alternately, if the lightsources are contained in 1852, 1853, then the coupling element 1856 maybe one or more electrical wires connecting to a power supply in 1857.Similarly, the detector outputs 1854, 1855 may be coupled to a detectoroutput unit 1859 with one or more coupling elements 1858, which may beone or more electrical wires or one or more light guides, such as afiber optic. This is just one example of a mouth guard design covering aplurality of teeth, but other embodiments may also be used and areintended to be covered by this disclosure. For instance, the position ofthe light source inputs and detector output ports could be exchanged, orsome mixture of locations of light source inputs and detector outputports could be used.

Other elements may be added to the human interface designs of FIG. 18and are also intended to be covered by this disclosure. For instance, inone embodiment it may be desirable to have replaceable inserts that maybe disposable. Particularly in a doctor's office or hospital setting,the same instrument may be used with a plurality of patients. Ratherthan disinfecting the human interface after each use, it may bepreferable to have disposable inserts that can be thrown away after eachuse. In one embodiment, a thin plastic coating material may enclose theclamp design of FIG. 18A or mouth guard design of FIG. 18B. The coatingmaterial may be inserted before each use, and then after the measurementis exercised the coating material may be peeled off and replaced. Such adesign may save the physician or user considerable time, while at thesame time provide the business venture with a recurring cost revenuesource. Any coating material or other disposable device may beconstructed of a material having suitable optical properties that may beconsidered during processing of the signals used to detect any anomaliesin the teeth.

Light Sources for Near Infrared

There are a number of light sources that may be used in the nearinfrared. To be more specific, the discussion below will consider lightsources operating in the so-called short wave infrared (SWIR), which maycover the wavelength range of approximately 1400 nm to 2500 nm. Otherwavelength ranges may also be used for the applications described inthis disclosure, so the discussion below is merely provided forexemplary types of light sources. The SWIR wavelength range may bevaluable for a number of reasons. First, the SWIR corresponds to atransmission window through water and the atmosphere. For example, 302in FIG. 3A and 1602 in FIG. 16A illustrate the water transmissionwindows. Also, through the atmosphere, wavelengths in the SWIR havesimilar transmission windows due to water vapor in the atmosphere.Second, the so-called “eye-safe” wavelengths are wavelengths longer thanapproximately 1400 nm. Third, the SWIR covers the wavelength range fornonlinear combinations of stretching and bending modes as well as thefirst overtone of C—H stretching modes. Thus, for example, glucose andketones among other substances may have unique signatures in the SWIR.Moreover, many solids have distinct spectral signatures in the SWIR, soparticular solids may be identified using stand-off detection or remotesensing. For instance, many explosives have unique signatures in theSWIR.

Different light sources may be selected for the SWIR based on the needsof the application. Some of the features for selecting a particularlight source include power or intensity, wavelength range or bandwidth,spatial or temporal coherence, spatial beam quality for focusing ortransmission over long distance, and pulse width or pulse repetitionrate. Depending on the application, lamps, light emitting diodes (LEDs),laser diodes (LD's), tunable LD's, super-luminescent laser diodes(SLDs), fiber lasers or super-continuum sources (SC) may beadvantageously used. Also, different fibers may be used for transportingthe light, such as fused silica fibers, plastic fibers, mid-infraredfibers (e.g., tellurite, chalcogenides, fluorides, ZBLAN, etc), or ahybrid of these fibers.

Lamps may be used if low power or intensity of light is required in theSWIR, and if an incoherent beam is suitable. In one embodiment, in theSWIR an incandescent lamp that can be used is based on tungsten andhalogen, which have an emission wavelength between approximately 500 nmto 2500 nm. For low intensity applications, it may also be possible touse thermal sources, where the SWIR radiation is based on the black bodyradiation from the hot object. Although the thermal and lamp basedsources are broadband and have low intensity fluctuations, it may bedifficult to achieve a high signal-to-noise ratio in a non-invasiveblood constituent measurement due to the low power levels. Also, thelamp based sources tend to be energy inefficient.

In another embodiment, LED's can be used that have a higher power levelin the SWIR wavelength range. LED's also produce an incoherent beam, butthe power level can be higher than a lamp and with higher energyefficiency. Also, the LED output may more easily be modulated, and theLED provides the option of continuous wave or pulsed mode of operation.LED's are solid state components that emit a wavelength band that is ofmoderate width, typically between about 20 nm to 40 nm. There are alsoso-called super-luminescent LEDs that may even emit over a much widerwavelength range. In another embodiment, a wide band light source may beconstructed by combining different LEDs that emit in differentwavelength bands, some of which could preferably overlap in spectrum.One advantage of LEDs as well as other solid state components is thecompact size that they may be packaged into.

In yet another embodiment, various types of laser diodes may be used inthe SWIR wavelength range. Just as LEDs may be higher in power butnarrower in wavelength emission than lamps and thermal sources, the LDsmay be yet higher in power but yet narrower in wavelength emission thanLEDs. Different kinds of LDs may be used, including Fabry-Perot LDs,distributed feedback (DFB) LDs, distributed Bragg reflector (DBR) LDs.Since the LDs have relatively narrow wavelength range (typically under10 nm), in one embodiment a plurality of LDs may be used that are atdifferent wavelengths in the SWIR. For example, in a preferredembodiment for non-invasive glucose monitoring, it may be advantageousto use LDs having emission spectra near some or all of the glucosespectral peaks (e.g., near 1587 nm, 1750 nm, 2120 nm, 2270 nm, and 2320nm). The various LDs may be spatially multiplexed, polarizationmultiplexed, wavelength multiplexed, or a combination of thesemultiplexing methods. Also, the LDs may be fiber pig-tailed or have oneor more lenses on the output to collimate or focus the light. Anotheradvantage of LDs is that they may be packaged compactly and may have aspatially coherent beam output. Moreover, tunable LDs that can tune overa range of wavelengths are also available. The tuning may be done byvarying the temperature, or electrical current may be used in particularstructures, such as distributed Bragg reflector LDs. In anotherembodiment, external cavity LDs may be used that have a tuning element,such as a fiber grating or a bulk grating, in the external cavity.

In another embodiment, super-luminescent laser diodes may provide higherpower as well as broad bandwidth. An SLD is typically an edge emittingsemiconductor light source based on super-luminescence (e.g., this couldbe amplified spontaneous emission). SLDs combine the higher power andbrightness of LDs with the low coherence of conventional LEDs, and theemission band for SLD's may be 5 to 100 nm wide, preferably in the 60 to100 nm range. Although currently SLDs are commercially available in thewavelength range of approximately 400 nm to 1700 nm, SLDs could and mayin the future be made to cover a broader region of the SWIR.

In yet another embodiment, high power LDs for either direct excitationor to pump fiber lasers and SC light sources may be constructed usingone or more laser diode bar stacks. As an example, FIG. 19 shows anexample of the block diagram 1900 or building blocks for constructingthe high power LDs. In this embodiment, one or more diode bar stacks1901 may be used, where the diode bar stack may be an array of severalsingle emitter LDs. Since the fast axis (e.g., vertical direction) maybe nearly diffraction limited while the slow-axis (e.g., horizontalaxis) may be far from diffraction limited, different collimators 1902may be used for the two axes.

Then, the brightness may be increased by spatially combining the beamsfrom multiple stacks 1903. The combiner may include spatialinterleaving, it may include wavelength multiplexing, or it may involvea combination of the two. Different spatial interleaving schemes may beused, such as using an array of prisms or mirrors with spacers to bendone array of beams into the beam path of the other. In anotherembodiment, segmented mirrors with alternate high-reflection andanti-reflection coatings may be used. Moreover, the brightness may beincreased by polarization beam combining 1904 the two orthogonalpolarizations, such as by using a polarization beam splitter. In oneembodiment, the output may then be focused or coupled into a largediameter core fiber. As an example, typical dimensions for the largediameter core fiber range from approximately 100 microns in diameter to400 microns or more. Alternatively or in addition, a custom beam shapingmodule 1905 may be used, depending on the particular application. Forexample, the output of the high power LD may be used directly 1906, orit may be fiber coupled 1907 to combine, integrate, or transport thehigh power LD energy. These high power LDs may grow in importancebecause the LD powers can rapidly scale up. For example, instead of thepower being limited by the power available from a single emitter, thepower may increase in multiples depending on the number of diodesmultiplexed and the size of the large diameter fiber. Although FIG. 19is shown as one embodiment, some or all of the elements may be used in ahigh power LD, or additional elements may also be used.

SWIR Super-Continuum Lasers

Each of the light sources described above have particular strengths, butthey also may have limitations. For example, there is typically atrade-off between wavelength range and power output. Also, sources suchas lamps, thermal sources, and LEDs produce incoherent beams that may bedifficult to focus to a small area and may have difficulty propagatingfor long distances. An alternative source that may overcome some ofthese limitations is an SC light source. Some of the advantages of theSC source may include high power and intensity, wide bandwidth,spatially coherent beam that can propagate nearly transform limited overlong distances, and easy compatibility with fiber delivery.

Supercontinuum lasers may combine the broadband attributes of lamps withthe spatial coherence and high brightness of lasers. By exploiting amodulational instability initiated supercontinuum (SC) mechanism, anall-fiber-integrated SC laser with no moving parts may be built usingcommercial-off-the-shelf (COTS) components. Moreover, the fiber laserarchitecture may be a platform where SC in the visible,near-infrared/SWIR, or mid-IR can be generated by appropriate selectionof the amplifier technology and the SC generation fiber. But until now,SC lasers were used primarily in laboratory settings since typicallylarge, table-top, mode-locked lasers were used to pump nonlinear mediasuch as optical fibers to generate SC light. However, those large pumplasers may now be replaced with diode lasers and fiber amplifiers thatgained maturity in the telecommunications industry.

In one embodiment, an all-fiber-integrated, high-powered SC light source2000 may be elegant for its simplicity (FIG. 20). The light may be firstgenerated from a seed laser diode 2001. For example, the seed LD 2001may be a distributed feedback laser diode with a wavelength near 1542 or1550 nm, with approximately 0.5-2.0 ns pulsed output, and with a pulserepetition rate between a kilohertz to about 100 MHz or more. The outputfrom the seed laser diode may then be amplified in a multiple-stagefiber amplifier 2002 comprising one or more gain fiber segments. In oneembodiment, the first stage pre-amplifier 2003 may be designed foroptimal noise performance. For example, the pre-amplifier 2003 may be astandard erbium-doped fiber amplifier or an erbium/ytterbium dopedcladding pumped fiber amplifier. Between amplifier stages 2003 and 2006,it may be advantageous to use band-pass filters 2004 to block amplifiedspontaneous emission and isolators 2005 to prevent spurious reflections.Then, the power amplifier stage 2006 may use a cladding-pumped fiberamplifier that may be optimized to minimize nonlinear distortion. Thepower amplifier fiber 2006 may also be an erbium-doped fiber amplifier,if only low or moderate power levels are to be generated.

The SC generation 2007 may occur in the relatively short lengths offiber that follow the pump laser. In one exemplary embodiment, the SCfiber length may range from a few millimeters to 100 m or more. In oneembodiment, the SC generation may occur in a first fiber 2008 where themodulational-instability initiated pulse break-up primarily occurs,followed by a second fiber 2009 where the SC generation and spectralbroadening primarily occurs.

In one embodiment, one or two meters of standard single-mode fiber (SMF)after the power amplifier stage may be followed by several meters of SCgeneration fiber. For this example, in the SMF the peak power may beseveral kilowatts and the pump light may fall in the anomalousgroup-velocity dispersion regime—often called the soliton regime. Forhigh peak powers in the dispersion regime, the nanosecond pulses may beunstable due to a phenomenon known as modulational instability, which isbasically parametric amplification in which the fiber nonlinearity helpsto phase match the pulses. As a consequence, the nanosecond pump pulsesmay be broken into many shorter pulses as the modulational instabilitytries to form soliton pulses from the quasi-continuous-wave background.Although the laser diode and amplification process starts withapproximately nanosecond-long pulses, modulational instability in theshort length of SMF fiber may form approximately 0.5 ps toseveral-picosecond-long pulses with high intensity. Thus, the few metersof SMF fiber may result in an output similar to that produced bymode-locked lasers, except in a much simpler and cost-effective manner.

The short pulses created through modulational instability may then becoupled into a nonlinear fiber for SC generation. The nonlinearmechanisms leading to broadband SC may include four-wave mixing orself-phase modulation along with the optical Raman effect. Since theRaman effect is self-phase-matched and shifts light to longerwavelengths by emission of optical photons, the SC may spread to longerwavelengths very efficiently. The short-wavelength edge may arise fromfour-wave mixing, and often times the short wavelength edge may belimited by increasing group-velocity dispersion in the fiber. In manyinstances, if the particular fiber used has sufficient peak power and SCfiber length, the SC generation process may fill the long-wavelengthedge up to the transmission window.

Mature fiber amplifiers for the power amplifier stage 2006 includeytterbium-doped fibers (near 1060 nm), erbium-doped fibers (near 1550nm), erbium/ytterbium-doped fibers (near 1550 nm), or thulium-dopedfibers (near 2000 nm). In various embodiments, candidates for SC fiber2009 include fused silica fibers (for generating SC between 0.8-2.7 μm),mid-IR fibers such as fluorides, chalcogenides, or tellurites (forgenerating SC out to 4.5 μm or longer), photonic crystal fibers (forgenerating SC between 0.4 and 1.7 μm), or combinations of these fibers.Therefore, by selecting the appropriate fiber-amplifier doping for 2006and nonlinear fiber 2009, SC may be generated in the visible,near-IR/SWIR, or mid-IR wavelength region.

The configuration 2000 of FIG. 20 is just one particular example, andother configurations can be used and are intended to be covered by thisdisclosure. For example, further gain stages may be used, and differenttypes of lossy elements or fiber taps may be used between the amplifierstages. In another embodiment, the SC generation may occur partially inthe amplifier fiber and in the pig-tails from the pump combiner or otherelements. In yet another embodiment, polarization maintaining fibers maybe used, and a polarizer may also be used to enhance the polarizationcontrast between amplifier stages. Also, not discussed in detail aremany accessories that may accompany this set-up, such as driverelectronics, pump laser diodes, safety shut-offs, and thermal managementand packaging.

One example of an SC laser that operates in the SWIR used in oneembodiment is illustrated in FIG. 21. This SWIR SC source 2100 producesan output of up to approximately 5 W over a spectral range of about 1.5to 2.4 microns, and this particular laser is made out of polarizationmaintaining components. The seed laser 2101 is a distributed feedback(DFB) laser operating near 1542 nm producing approximately 0.5nanosecond (ns) pulses at an about 8 MHz repetition rate. Thepre-amplifier 2102 is forward pumped and uses about 2 m length oferbium/ytterbium cladding pumped fiber 2103 (often also called dual-corefiber) with an inner core diameter of 12 microns and outer core diameterof 130 microns. The pre-amplifier gain fiber 2103 is pumped using a 10 W940 nm laser diode 2105 that is coupled in using a fiber combiner 2104.

In this particular 5 W unit, the mid-stage between amplifier stages 2102and 2106 comprises an isolator 2107, a band-pass filter 2108, apolarizer 2109 and a fiber tap 2110. The power amplifier 2106 uses a 4 mlength of the 12/130 micron erbium/ytterbium doped fiber 2111 that iscounter-propagating pumped using one or more 30 W 940 nm laser diodes2112 coupled in through a combiner 2113. An approximately 1-2 meterlength of the combiner pig-tail helps to initiate the SC process, andthen a length of PM-1550 fiber 2115 (polarization maintaining,single-mode, fused silica fiber optimized for 1550 nm) is spliced 2114to the combiner output.

If an output fiber of about 10 m in length is used, then the resultingoutput spectrum 2200 is shown in FIG. 22. The details of the outputspectrum 2200 depend on the peak power into the fiber, the fiber length,and properties of the fiber such as length and core size, as well as thezero dispersion wavelength and the dispersion properties. For example,if a shorter length of fiber is used, then the spectrum actually reachesto longer wavelengths (e.g., a 2 m length of SC fiber broadens thespectrum to ˜2500 nm). Also, if extra-dry fibers are used with less O—Hcontent, then the wavelength edge may also reach to a longer wavelength.To generate more spectrum toward the shorter wavelengths, the pumpwavelength (in this case ˜1542 nm) should be close to the zerodispersion wavelength in the fiber. For example, by using a dispersionshifted fiber or so-called non-zero dispersion shifted fiber, the shortwavelength edge may shift to shorter wavelengths.

Although one particular example of a 5 W SWIR-SC has been described,different components, different fibers, and different configurations mayalso be used consistent with this disclosure. For instance, anotherembodiment of the similar configuration 2100 in FIG. 21 may be used togenerate high powered SC between approximately 1060 and 1800 nm. Forthis embodiment, the seed laser 2101 may be a 1064 nm distributedfeedback (DFB) laser diode, the pre-amplifier gain fiber 2103 may be aytterbium-doped fiber amplifier with 10/125 microns dimensions, and thepump laser 2105 may be a 10 W 915 nm laser diode. In the mid-stage, amode field adapter may be included in addition to the isolator 2107,band pass filter 2108, polarizer 2109 and tap 2110. The gain fiber 2111in the power amplifier may be a 20 m length of ytterbium-doped fiberwith 25/400 microns dimension for example. The pump 2112 for the poweramplifier may be up to six pump diodes providing 30 W each near 915 nm,for example. For this much pump power, the output power in the SC may beas high as 50 W or more.

In another embodiment, it may be desirous to generate high power SWIR SCover 1.4-1.8 microns and separately 2-2.5 microns (the window between1.8 and 2 microns may be less important due to the strong water andatmospheric absorption). For example, the top SC source of FIG. 23 canlead to bandwidths ranging from about 1400 nm to 1800 nm or broader,while the lower SC source of FIG. 23 can lead to bandwidths ranging fromabout 1900 nm to 2500 nm or broader. Since these wavelength ranges areshorter than about 2500 nm, the SC fiber can be based on fused silicafiber. Exemplary SC fibers include standard single-mode fiber SMF,high-nonlinearity fiber, high-NA fiber, dispersion shifted fiber,dispersion compensating fiber, and photonic crystal fibers.Non-fused-silica fibers can also be used for SC generation, includingchalcogenides, fluorides, ZBLAN, tellurites, and germanium oxide fibers.

In one embodiment, the top of FIG. 23 illustrates a block diagram for anSC source 2300 capable of generating light between approximately 1400and 1800 nm or broader. As an example, a pump fiber laser similar toFIG. 21 can be used as the input to a SC fiber 2309. The seed laserdiode 2301 can comprise a DFB laser that generates, for example, severalmilliwatts of power around 1542 or 1553 nm. The fiber pre-amplifier 2302can comprise an erbium-doped fiber amplifier or an erbium/ytterbiumdoped double clad fiber. In this example a mid-stage amplifier 2303 canbe used, which can comprise an erbium/ytterbium doped double-clad fiber.A bandpass filter 2305 and isolator 2306 may be used between thepre-amplifier 2302 and mid-stage amplifier 2303. The power amplifierstage 2304 can comprise a larger core size erbium/ytterbium dopeddouble-clad fiber, and another bandpass filter 2307 and isolator 2308can be used before the power amplifier 2304. The output of the poweramplifier can be coupled to the SC fiber 2309 to generate the SC output2310. This is just one exemplary configuration for an SC source, andother configurations or elements may be used consistent with thisdisclosure.

In yet another embodiment, the bottom of FIG. 23 illustrates a blockdiagram for an SC source 2350 capable of generating light betweenapproximately 1900 and 2500 nm or broader. As an example, the seed laserdiode 2351 can comprise a DFB or DBR laser that generates, for example,several milliwatts of power around 1542 or 1553 nm. The fiberpre-amplifier 2352 can comprise an erbium-doped fiber amplifier or anerbium/ytterbium doped double-clad fiber. In this example a mid-stageamplifier 2353 can be used, which can comprise an erbium/ytterbium dopeddouble-clad fiber. A bandpass filter 2355 and isolator 2356 may be usedbetween the pre-amplifier 2352 and mid-stage amplifier 2353. The poweramplifier stage 2354 can comprise a thulium doped double-clad fiber, andanother isolator 2357 can be used before the power amplifier 2354. Notethat the output of the mid-stage amplifier 2353 can be approximatelynear 1550 nm, while the thulium-doped fiber amplifier 2354 can amplifywavelengths longer than approximately 1900 nm and out to about 2100 nm.Therefore, for this configuration wavelength shifting may be requiredbetween 2353 and 2354. In one embodiment, the wavelength shifting can beaccomplished using a length of standard single-mode fiber 2358, whichcan have a length between approximately 5 and 50 meters, for example.The output of the power amplifier 2354 can be coupled to the SC fiber2359 to generate the SC output 2360. This is just one exemplaryconfiguration for an SC source, and other configurations or elements canbe used consistent with this disclosure. For example, the variousamplifier stages can comprise different amplifier types, such as erbiumdoped fibers, ytterbium doped fibers, erbium/ytterbium co-doped fibersand thulium doped fibers. One advantage of the SC lasers illustrated inFIGS. 20-23 are that they may use all-fiber components, so that the SClaser can be all-fiber, monolithically integrated with no moving parts.The all-integrated configuration can consequently be robust andreliable.

FIGS. 20-23 are examples of SC light sources that may be advantageouslyused for SWIR light generation in various medical diagnostic andtherapeutic applications. However, many other versions of the SC lightsources may also be made that are intended to also be covered by thisdisclosure. For example, the SC generation fiber could be pumped by amode-locked laser, a gain-switched semiconductor laser, an opticallypumped semiconductor laser, a solid state laser, other fiber lasers, ora combination of these types of lasers. Also, rather than using a fiberfor SC generation, either a liquid or a gas cell might be used as thenonlinear medium in which the spectrum is to be broadened.

Even within the all-fiber versions illustrated such as in FIG. 21,different configurations could be used consistent with the disclosure.In an alternate embodiment, it may be desirous to have a lower costversion of the SWIR SC laser of FIG. 21. One way to lower the cost couldbe to use a single stage of optical amplification, rather than twostages, which may be feasible if lower output power is required or thegain fiber is optimized. For example, the pre-amplifier stage 2102 mightbe removed, along with at least some of the mid-stage elements. In yetanother embodiment, the gain fiber could be double passed to emulate atwo stage amplifier. In this example, the pre-amplifier stage 2102 mightbe removed, and perhaps also some of the mid-stage elements. A mirror orfiber grating reflector could be placed after the power amplifier stage2106 that may preferentially reflect light near the wavelength of theseed laser 2101. If the mirror or fiber grating reflector can transmitthe pump light near 940 nm, then this could also be used instead of thepump combiner 2113 to bring in the pump light 2112. The SC fiber 2115could be placed between the seed laser 2101 and the power amplifierstage 2106 (SC is only generated after the second pass through theamplifier, since the power level may be sufficiently high at that time).In addition, an output coupler may be placed between the seed laserdiode 2101 and the SC fiber, which now may be in front of the poweramplifier 2106. In a particular embodiment, the output coupler could bea power coupler or divider, a dichroic coupler (e.g., passing seed laserwavelength but outputting the SC wavelengths), or a wavelength divisionmultiplexer coupler. This is just one further example, but a myriad ofother combinations of components and architectures could also be usedfor SC light sources to generate SWIR light that are intended to becovered by this disclosure.

Wireless Link to the Cloud

The non-invasive blood constituent or analytes measurement device mayalso benefit from communicating the data output to the “cloud” (e.g.,data servers and processors in the web remotely connected) via wiredand/or wireless communication strategies. The non-invasive devices maybe part of a series of biosensors applied to the patient, andcollectively these devices form what might be called a body area networkor a personal area network. The biosensors and non-invasive devices maycommunicate to a smart phone, tablet, personal data assistant, computer,and/or other microprocessor-based device, which may in turn wirelesslyor over wire and/or fiber optically transmit some or all of the signalor processed data to the internet or cloud. The cloud or internet may inturn send the data to doctors or health care providers as well as thepatients themselves. Thus, it may be possible to have a panoramic,high-definition, relatively comprehensive view of a patient that doctorscan use to assess and manage disease, and that patients can use to helpmaintain their health and direct their own care.

In a particular embodiment 2400, the physiological measurement device ornon-invasive blood constituent measurement device 2401 may comprise atransmitter 2403 to communicate over a first communication link 2404 inthe body area network or personal area network to a receiver in a smartphone, tablet cell phone, PDA, or computer 2405. For the measurementdevice 2401, it may also be advantageous to have a processor 2402 toprocess some of the physiological data, since with processing the amountof data to transmit may be less (hence, more energy efficient). Thefirst communication link 2404 may operate through the use of one of manywireless technologies such as Bluetooth, Zigbee, WiFi, IrDA (infrareddata association), wireless USB, or Z-wave, to name a few.Alternatively, the communication link 2404 may occur in the wirelessmedical band between 2360 and 2390 MHz, which the FCC allocated formedical body area network devices, or in other designated medical deviceor WMTS bands. These are examples of devices that can be used in thebody area network and surroundings, but other devices could also be usedand are included in the scope of this disclosure.

The personal device 2405 may store, process, display, and transmit someof the data from the measurement device 2401. The device 2405 maycomprise a receiver, transmitter, display, voice control and speakers,and one or more control buttons or knobs and a touch screen. Examples ofthe device 2405 include smart phones such as the Apple iPhones® orphones operating on the Android or Microsoft systems. In one embodiment,the device 2405 may have an application, software program, or firmwareto receive and process the data from the measurement device 2401. Thedevice 2405 may then transmit some or all of the data or the processeddata over a second communication link 2406 to the internet or “cloud”2407. The second communication link 2406 may advantageously comprise atleast one segment of a wireless transmission link, which may operateusing WiFi or the cellular network. The second communication link 2406may additionally comprise lengths of fiber optic and/or communicationover copper wires or cables.

The internet or cloud 2407 may add value to the measurement device 2401by providing services that augment the physiological data collected. Ina particular embodiment, some of the functions performed by the cloudinclude: (a) receive at least a fraction of the data from the device2405; (b) buffer or store the data received; (c) process the data usingsoftware stored on the cloud; (d) store the resulting processed data;and (e) transmit some or all of the data either upon request or based onan alarm. As an example, the data or processed data may be transmitted2408 back to the originator (e.g., patient or user), it may betransmitted 2409 to a health care provider or doctor, or it may betransmitted 2410 to other designated recipients.

The cloud 2407 may provide a number of value-add services. For example,the cloud application may store and process the physiological data forfuture reference or during a visit with the healthcare provider. If apatient has some sort of medical mishap or emergency, the physician canobtain the history of the physiological parameters over a specifiedperiod of time. In another embodiment, if the physiological parametersfall out of acceptable range, alarms may be delivered to the user 2408,the healthcare provider 2409, or other designated recipients 2410. Theseare just some of the features that may be offered, but many others maybe possible and are intended to be covered by this disclosure. As anexample, the device 2405 may also have a GPS sensor, so the cloud 2407may be able to provide time, data and position along with thephysiological parameters. Thus, if there is a medical emergency, thecloud 2407 could provide the location of the patient to the healthcareprovider 2409 or other designated recipients 2410. Moreover, thedigitized data in the cloud 2407 may help to move toward what is oftencalled “personalized medicine.” Based on the physiological parameterdata history, medication or medical therapies may be prescribed that arecustomized to the particular patient.

Beyond the above benefits, the cloud application 2407 and application onthe device 2405 may also have financial value for companies developingmeasurement devices 2401 such as a non-invasive blood constituentmonitor. In the case of glucose monitors, the companies make themajority of their revenue on the measurement strips. However, with anon-invasive monitor, there is no need for strips, so there is less ofan opportunity for recurring costs (e.g., the razor/razor blade modeldoes not work for non-invasive devices). On the other hand, people maybe willing to pay a periodic fee for the value-add services provided onthe cloud 2407. Diabetic patients, for example, would probably bewilling to pay a periodic fee for monitoring their glucose levels,storing the history of the glucose levels, and having alarm warningswhen the glucose level falls out of range. Similarly, patients takingketone bodies supplement for treatment of disorders characterized byimpaired glucose metabolism (e.g., Alzheimer's, Parkinson's,Huntington's or ALS) may need to monitor their ketone bodies level.These patients would also probably be willing to pay a periodic fee forthe value-add services provided on the cloud 2407. Thus, by leveragingthe advances in wireless connectivity and the widespread use of handhelddevices such as smart phones that can wirelessly connect to the cloud,businesses can build a recurring cost business model even usingnon-invasive measurement devices.

Described herein are just some examples of the beneficial use ofnear-infrared or SWIR lasers for non-invasive monitoring of glucose,ketones, HbA1 c and other blood constituents. However, many othermedical procedures can use the near-infrared or SWIR light consistentwith this disclosure and are intended to be covered by the disclosure.

Although the present disclosure has been described in severalembodiments, a myriad of changes, variations, alterations,transformations, and modifications may be suggested to one skilled inthe art, and it is intended that the present disclosure encompass suchchanges, variations, alterations, transformations, and modifications asfalling within the spirit and scope of the appended claims.

While exemplary embodiments are described above, it is not intended thatthese embodiments describe all possible forms of the disclosure. Rather,the words used in the specification are words of description rather thanlimitation, and it is understood that various changes may be madewithout departing from the spirit and scope of the disclosure.Additionally, the features of various implementing embodiments may becombined to form further embodiments of the disclosure. While variousembodiments may have been described as providing advantages or beingpreferred over other embodiments with respect to one or more desiredcharacteristics, as one skilled in the art is aware, one or morecharacteristics may be compromised to achieve desired system attributes,which depend on the specific application and implementation. Theseattributes include, but are not limited to: cost, strength, durability,life cycle cost, marketability, appearance, packaging, size,serviceability, weight, manufacturability, ease of assembly, etc. Theembodiments described herein that are described as less desirable thanother embodiments or prior art implementations with respect to one ormore characteristics are not outside the scope of the disclosure and maybe desirable for particular applications.

What is claimed is:
 1. A diagnostic system comprising: a light sourceconfigured to generate an output optical beam, comprising: one or moresemiconductor sources configured to generate an input beam; one or moreoptical amplifiers configured to receive at least a portion of the inputbeam and to deliver an intermediate beam to an output end of the one ormore optical amplifiers; one or more optical fibers configured toreceive at least a portion of the intermediate beam and to deliver atleast the portion of the intermediate beam to a distal end of the one ormore optical fibers to form a first optical beam; a nonlinear elementconfigured to receive at least a portion of the first optical beam andto broaden a spectrum associated with the at least a portion of thefirst optical beam to at least 10 nanometers through a nonlinear effectin the nonlinear element to form the output optical beam with an outputbeam broadened spectrum; and wherein at least a portion of the outputbeam broadened spectrum comprises a short-wave infrared wavelengthbetween approximately 1400 nanometers and approximately 2500 nanometers,and wherein at least a portion of the one of more fibers is a fusedsilica fiber with a core diameter less than approximately 400 microns;an interface device configured to receive a received portion of theoutput optical beam and to deliver a delivered portion of the outputoptical beam to a sample, wherein the delivered portion of the outputoptical beam is configured to generate a spectroscopy output beam fromthe sample; and a receiver configured to receive at least a portion ofthe spectroscopy output beam having a bandwidth of at least 10nanometers and to process the portion of the spectroscopy output beam togenerate an output signal representing at least in part a property ofhydro-carbon bonds.
 2. The system of claim 1, wherein the interfacedevice further comprises a replaceable insert.
 3. The system of claim 1,wherein the sample comprises at least in part enamel, dentine and blood,and wherein the output signal represents at least in part a property ofthe blood.
 4. The system of claim 1, wherein the input beam comprises arepetition rate between approximately one kilohertz and approximately100 MHz.
 5. The system of claim 1, wherein the receiver furthercomprises a wireless transmitter configured to communicate a wirelesssignal associated with the output signal to a network.
 6. A measurementsystem comprising: a light source generating an output optical beam,comprising: a plurality of semiconductor sources generating an inputoptical beam; a multiplexer configured to receive at least a portion ofthe input optical beam and to form an intermediate optical beam; one ormore fibers configured to receive at least a portion of the intermediateoptical beam and to form the output optical beam, wherein the outputoptical beam comprises one or more optical wavelengths, at least aportion of which are between approximately 1400 nanometers andapproximately 2500 nanometers, and wherein at least a portion of the oneor more fibers is a fused silica fiber with a core diameter less thanapproximately 400 microns; and wherein the output optical beam has abroadened spectrum relative to the intermediate optical beam of at least10 nanometers; an interface device configured to receive a receivedportion of the output optical beam and to deliver a delivered portion ofthe output optical beam to a sample comprising at least in part enamel,dentine and pulp, wherein the delivered portion of the output opticalbeam is configured to generate a spectroscopy output beam from thesample; and a receiver configured to receive at least a portion of thespectroscopy output beam having a bandwidth of at least 10 nanometersand to process the portion of the spectroscopy output beam to generatean output signal representing at least in part a property of bloodcontained within the pulp.
 7. The system of claim 6, wherein the lightsource comprises a super-continuum laser.
 8. The system of claim 6,wherein the light source comprises a super-luminescent diode.
 9. Thesystem of claim 6, wherein the light source comprises a light emittingdiode.
 10. The system of claim 6, wherein the one of more opticalwavelengths comprise a short-wave infrared wavelength.
 11. The system ofclaim 6, wherein the property of the blood comprises a glucose level.12. The system of claim 11, wherein at least a portion of the one ormore optical wavelengths is near 1587 nanometers or near 1750nanometers.
 13. The system of claim 11, wherein at least a portion ofthe one or more optical wavelengths is near 2120 nanometers, near 2270nanometers, or near 2320 nanometers.
 14. The system of claim 6, whereinthe delivered portion of the output optical beam is transmitted throughthe sample.
 15. The system of claim 6, wherein the interface devicefurther comprises a replaceable insert.
 16. The system of claim 6,wherein the receiver is configured to process the portion of thespectroscopy output beam using a pattern matching methodology.
 17. Amethod of measuring comprising: generating an output optical beam,comprising: generating an input optical beam from a plurality ofsemiconductor sources; multiplexing at least a portion of the inputoptical beam and forming an intermediate optical beam; guiding at leasta portion of the intermediate optical beam using one or more fibers, atleast a portion of which comprises fused silica fiber with a corediameter less than approximately 400 microns and forming the outputoptical beam, wherein the output optical beam comprises one or moreoptical wavelengths, at least a portion of which are betweenapproximately 1400 nanometers and approximately 2500 nanometers; andbroadening the spectrum of at least a portion of the intermediateoptical beam to at least 10 nanometers to form the output optical beamwith an output beam broadened spectrum; receiving a received portion ofthe output optical beam and delivering a delivered portion of the outputoptical beam to a sample, wherein the sample comprises at least in partenamel, dentine and pulp; generating a spectroscopy output beam from thesample; receiving at least a portion of the spectroscopy output beamhaving a bandwidth of at least 10 nanometers; and processing the portionof the spectroscopy output beam and generating an output signalrepresenting at least in part a property of blood contained within thepulp.
 18. The method of claim 17, wherein the one or more opticalwavelengths comprise a short-wave infrared wavelength.
 19. The method ofclaim 17, wherein the property of the blood comprises a glucose level.20. The method of claim 17, further comprising communicating a wirelesssignal associated with the output signal to a network.